Animal feed and process

ABSTRACT

WHEREIN R is selected from the group consisting of cyano, nitro, dialkylamino in which alkyl is of 1 to 3 carbon atoms, inclusive, alkoxy in which the alkyl moiety is defined as above, -COOR&#39;&#39;&#39;&#39; in which R&#39;&#39;&#39;&#39; is alkyl defined as above; wherein R1 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, inclusive; and wherein R2R3, R4, and R5 are selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl-amino and dialkylamino in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive, a pharmacologically acceptable acid addition salt thereof and the N-5 oxide thereof in combination with the nutrient feed.   An animal feed for increasing meat, milk, or egg production comprising a compound of the group consisting of a 1-substituted 6-phenyl-4H-s-triazolo(4,3-a)-(1,4)benzodiazepine of the formula:

United States Patent 1191 Collins ANIMAL FEED AND PROCESS [75] Inventor: Robert J. Collins, Portage, Mich. [73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Aug. 9, 1971 [21] Appl. No.: 170,323

[52] US. Cl. 424/269 [51] Int. Cl A61k 27/00 [58] Field of Search 424/251,.269

[56] References Cited UNITED STATES PATENTS 3,703,525 11/1972 Tawada et a1 260/3 08 R FOREIGN PATENTS OR APPLICATIONS 6,916,543 5/1970 Netherlands ..'424/269 2,012,190 9/1970 Germany 260/380 OTHER PUBLICATIONS Archer et a1., Chem. Reviews, Vol. 68, pp. 754, 759- 760, (1968).

[57] ABSTRACT An animal feed for increasing meat, milk, or egg production comprising a compound of the group consisting of a l-substituted 6-pheny1-4H-s-triazolo[4,3-a]- 111] 3,821,388 June 28, 1974 1,4]benzodiazepine of the formula:

R Formula 1 wherein R is selected from the group consisting of cyano, nitro, dialkylamino in which alkyl is of l to 3 carbon atoms, inclusive, alkoxy in which the alkyl moiety is defined as above, -COOR" in which R" is alkyl defined as above; wherein R is selected from the group consisting of hydrogen and alkyl of l to 3 carbon atoms, inclusive; and wherein R R R and R are selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyI-amino and dialkylamino in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive, a pharmacologically acceptable acid addition salt thereof and the N5 oxide thereof in combination with the nutrient feed.

6 Claims, No Drawings 1 ANIMAL FEED AND PROCESS CROSS REFERENCE TO RELATED APPLICATIONS This application is related to copending U.S. application Ser. No. 138,278, filed Apr. 28, 1971, now abandoned which discloses compounds of the Formula 1 and methods for their preparation.

BRIEF SUMMARY OF THE INVENTION DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, minerals, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efficiently with respect to feed intake at a lower cost and without undesirable side effects.

It is now possible by use of the present invention to obtain unexpected results in the feeding of meatproducing, milk-producing, or egg-laying animals; that is to say, an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efficiency, can be obtained by the addition of minute quantities of a compound of the Formula 1 to the animals usual nutrient feed.

Compounds of the Formula 1 can be prepared by .methods disclosed in U.S. application Ser. No.

138,278, filed Apr. 28, 1971, now abandoned.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals when they are starting on solid food and, of course, after weaning. Feeding of the compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula l in the feed composition is determined with re gard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula 1 is employed in the finished feed that will supply the animal with a daily intake of from about 0.015 mg. to about 250 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

Range Preferred Animal Daily Dose/Head, mg. Daily Dose, mg.

Swine (birth to 8 weeks) 0.125 12.5 0.7 Swine (40 to 2001bs.) 0.775 72.5 4.0 Chickens (growing 0-8 weeks) 0.015 1.5 0.1 Hens (laying) 0.03 3.0 0.15 Turkeys (growing O-24 Weeks) 0.1 5.0 0.25 Beef Cattle (fattening) 2.5 250 14.0 Calves (012 weeks) 03 30 1.5 Dairy Cattle (lactation) 2.5 250 14.0 Lambs (fattening) 0.19 19' 1.0

The foregoing dosage can generally be accomplished by providing from about mg. to about 12,500 mg. of a compound of the Formula 1 per ton of finished feed.

Advantageously a compound of the Formula 1 is supplied in the form of a liquid or solid premix wherein the concentration is 2,000 times greater than the desired final concentration of the feed. For example, the compound of Formula 1 can be dissolved or suspended in a fluid vehicle such as corn oil, cottonseed oil, molasses, distillers solubles and the like to prepare a fluid premix. Alternatively, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid diluent such as sucrose, lactose, starch, corn meal, flour, calcium carbonate, soybean meal and the like.

EXAMPLE 1 A diet for fattening lambs is prepared from the following types and amounts of ingredients:

Ground ear corn 82.05% Alfalfa meal 10.0 '71 Soybean oil meal 44% 7.0 71 Ground limestone 0.3 7! Salt 0.6 Trace mineral mixture 0.05%

Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0.4: l, 0.24; Zn, 0.7.

EXAMPLE 2 A chicken feed for broilers is prepared from the fol lowing types and amounts of ingredients:

Yellow corn meal 67.35%

Consisting of l6.0 gm. Vitamin A supplement l units/mg. 3.6 gm. Vitamin D supplement (l5,000 units/gm.); 7.] gm. riboflavin supplement (1 gm. riboflavin per ounce); 500 mg. niacin.

EXAMPLE 3 A fattening feed for 800 pound yearling cattle is prepared from the following types and amounts of ingredients:

Ground ear corn 89.757: Soybean oil meal. 44% 9.0 7( Ground limestone 0.7 /1 Salt 0.5 7: Trace mineral mixture 0.0571

Contains the following percent olminerals: Mn. l2; Co. 0.08; Fe, 5.0; Cu. 04; l. 0.24; Zn, 0.7.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.5 gm. of 8-chloro-6-phenyl-4H-s-triazolo[4,3-

a][ l,4]benzodiazepinel -acetonitrile with sufficient wheat flour to make 1 pound.

The feeding composition so prepared supplies 1.5 mg. of 8-chloro-6-phenyl-4H-s-triazolo[4,3- a][ l ,4]benzodiazepine-l-acetonitrile per pound, or about 3.3 parts per million.

Cattle are to receive the foregoing feed ad libitum together with 5 lb. of hay per head per day and when so fed have an increased rate of weight gain and improved utilization of feed.

EXAMPLE 4 A swine diet for growing hogs of 40 to 100 pounds body weight is prepared from the following types and amounts of ingredients:

Corn. ground 78.157: Soybean oil meal. 44% 17.0 71 Meat and bone scraps, 50% 3.0 7r Oyster shell flour 0.4 Bone meal 0.5 71 Salt 0.5 Trace mineral mixture 0.05% Zinc oxide 001% Vitamin A and D supplement 0.25% B Vitamin supplement 0.05%

Vitamin 8, supplement Contains the following percent of mineralsc-Mn. I2; Co. 0.08; Fe. 5.0; Cu, 04; l, 0.24: Zn. 0.7. Contains 300 USP units D /Gm. and I500 l.U.A./Gm.

Continued "Contains per 1b.: riboflavin. 2000 mg.; calcium paniothenate, 4000 mg; niacin; 9000 mg; and choline chloride l0.000 mg. Contains 6 mg. Vitamin B per lb.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.75 gm. of 8-chloro-6-phenyl-4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine-l-acetonitrile with sufficient ground limestone to make one pound.

The feeding composition so prepared supplies 0.75 mg. of 8-chloro-6-phenyl-4H-s-triazolo[4,3- a][l,4]benzodiazepine-l-acetonitrile per pound, or about 1.65 parts per million.

The foregoing composition is usefully fed to hogs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 5 Following the procedure of the preceding Examples 3 l to 4, inclusive, animal feeds are similarly prepared substituting equimolar amounts of:

8-chlorol ethoxymethyl )-6-phenyl-4H-striazolo[4,3-a]-[ 1,4]benzodiazepine;

8-chloro-6-phenyl-4H-s-triazolo[4,3- a][ l,4]benzodiazepine-l-acetic acid methyl ester; 8-chlorol -[diethylaminomethyl]-6-phenyl-4H-stria2olo-[4,3-a][ l ,4]benzodiazepine;'

8-nitrol diethylaminomethyl )-6-phenyl-4H-striazolo-[4,3-a][1,4]benzodiazepine;

9-ethylthiol propoxymethyl )-6-(o-chlo'rophenyl 4H-s-triazolo[4,3-a][ 1,4]benzodia1epine;

7-fluorol methoxymethyl)-6-( o-bromophenyl 4H-s-triazolo[4,3-a][ 1,4]ben2odiazepine;

7-trifluoromethyl-6-[ m-( methylsulfonyl )phenyl -4H- s-triazolo[4,3-a][ 1,4]benzodiazepinel -acetonitrile; 9-iodol-(methoxymethyl )-6-( 2,6-difluorophenyl 4l-l-s-triazolo[4,3-a][ l ,4]benzodiazepine;

7-ethylsulfinyll isopropoxymethyl )-6-[ p- (trifluoromethyl)phenyl]-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine;

9-methyll dipropylaminomethyl )-6-( pisopropylphenyl)-4H-s-triazolo[4,3- a] 1,4]benzodiazepine;

7,9-diethyl-6-(2,4-diethylphenyl)-4H-s-triazolo[4,3- a]-[ l ,4]benzodiazepinel-acetonitrile; 7,8-dinitro-6- (2,4-dibromophenyl)-4H-s-triazolo[4,3-a]- 1,4]benzodiazepinel -acetonitrile;

7-trifluoromethyl-6-[ m-( methylsulfonyl )phenyl]-4H- s-triazolo[4,3-a][ 1,4]benzodiazepinel-acetic acid ethyl ester;

7,9-diethy1-6-(2,4-diethylphenyl)-4H-s-triazolo[4,3- a]-[1,4]benzodiazepine-l-acetic acid propyl ester;

7,8-dinitro-6-( 2 ,4-dibromophenyl )-4H-striazolo[4,3-a]-[ l ,4]benzodiazepinel -acetic methyl ester;

8-chlorol-( methylthio )methyl-6-(o-chlorophenyl 4H-s-'triazolo[4,3-a][ l ,4]benzodiazepine;

9-nitrol-(ethylthio)methyl-6-[m-( propylsulfonyl phenyl]-4H-striazolo[4,3-a][ 1,4]benzodiazepine;

l0-chlorol -(methylthio)methyl-6-( misopropylphenyl)-4H-s-triaz0lo[4,3- a][ l ,4]benzodiazepine;

9-(dipropylamino)- l dimethylamino)methyl-6-[p- (propionylamino)phenyl]-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine;

acid

7-( ethylsulfonyl l-(dipropylamino)methyl-6-(ocyanophenyl)-4ll-s-triazolo[4,3- 5 a] l ,4]benzodiazepine;

4-propyl-1-(diisopropylamino)methyl-6-[m- (methylthio)-phenyl]-4H-s-triazolo[4,3-

a] 1 ,4]benzodiazepine;

l0-fluoro-7-chlorol -ethoxymethyl-6-[ p- (trifluoromethyl)phenyl]-4l-I-s-triazolo[4,3-

a][ 1,4]benzodiazepine;

7 ,9-diethoxyl -methoxymethyl-6-( m-ethoxyphenyl 4H-s-triazolo[4,3-a] [l ,4]benzodiazepine;

7-( propylthio)-6-(m-iodophenyl)-4l-l-s-triazolo[4,3- a]-[ 1,4] enzodiazepine- 1 -acetonitrile;

8-(acetylamino)-6-(p-iodophenyl)-4H-stria2olo[4,3-a]-[ l,4]benzodiazepine-l-acetonitrile;

4-propyll -nitromethyl-6-(oiodophenyl )-4H-striazolo-[4,3-a][ l,4]benzodiazepine;

4-ethyl-1-(methylthio)methyl-6-[oethylthio)phenyl]-4l-l-s-triazolo[4,3- a][ 1,4]benzodiazepine;

4-methyl-7, l O-dichlorol -(ethylthio)methyl-6-(misopropoxyphenyl)-4H-s-triazolo[4,3- a][ l ,4]benzodiazepine;

9-(propionylamino)--- propylthio )methyl-6-[ m-(propylthio)phenyl ]-4H-striazolo[4,3-a][1,4]benzodiazepine;

7-(diisopropylamino)-l-nitromethyl-6-[p- (dipropylamino)-phenyl]-4H-s-triaz0lo[4,3- a][ 1,4]benzodiazepine;

4-isopropyl-7,9-diiodo-6-phenyl-4H-s-triazolo[4,3- a]-[ l ,4]benzodiazepine-l-acetic acid ethyl ester;

8-chloro-6-(3,4-dimethylphenyl)-4H-striazolo[4,3- a]-[ l ,4]benzodiazepinelacetic propyl ester;

6-( 2-methyl-4-methoxyphenyl )-4H-s-triazolo[ 4,3-a l ,4 lbenzodiazepinel -acetonitrile;

S-methylthiol -isopropoxymethyl-6-phenyl-4H-striazolo-[4,3-a][ 1,4]benzodiazepine; 40

4,8-dimethoxyl -ethoxymethyl-6-phenyl-4H-stria2o]o-[4,3-a][1,4]benzodiazepine for the 8-chloro- 6-phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine-lacetonitrile of the examples.

I claim:

1. A process for increasing meat, milk, or egg production in a healthy meat-producing, milk-producing, or egg-laying animal comprising the feeding thereto of from about 0.015 to about 250 mg/day of a compound selected from the group consisting of a l-substituted-6- phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine of the formula:

9 8 e 5 R4 7 R2 wherein R is selected from the group consisting of cyano, nitro, dialkylamino in which alkyl is of l to 3 carbon atoms, inclusive, alkoxy in which the alkyl moiety is defined as above, alkylthio in which the alkyl moiety is defined as above, -COOR" in which R is alkyl defined as above; wherein R, is selected from the group consisting of hydrogen and alkyl of l to 3 carbon atoms, inclusive; and wherein R R R and R are selected from the group consisting of hydrogen, alkyl of l to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino and dialkylamino in which the carbon chain moieties are of l to 3 carbon atoms, inclusive; and a pharmacologically acceptable acid addition salt thereof in combination with the nutrient animal feed.

2. The process of claim 1 wherein the member selected is in a concentration of from mg. to 12,500 mg. per pound of nutrient carrier in the form of a prelTllX.

3. The process of claim 1 wherein the member selected is in the concentration from 250 mg. to 25,000 mg. per ton of feed.

4. The process of claim 1 wherein the compound is 8-chloro-6-phenyl-4H-s-triazolo[4,3-a]- 1,4]benzodiazepine- 1 -acetonitrile.

5. The process of claim 2 wherein the compound is 8-chloro-6-phenyl-4H-s-triazolo[4,3-a1- l ,4]benzodiazepinel -acetonitrile.

6. The process of claim 3 wherein the compound is 8-chloro-6-phenyl-4H-s-triazolo[4,3-a]- l ,4]benzodiazepine- 1 -acetonitrile. 

2. The process of claim 1 wherein the member selected is in a concentration of from 125 mg. to 12,500 mg. per pound of nutrient carrier in the form of a premix.
 3. The process of claim 1 wherein the member selected is in the concentration from 250 mg. to 25,000 mg. per ton of feed.
 4. The process of claim 1 wherein the compound is 8-chloro-6-phenyl-4H-s-triazolo(4,3-a)-(1,4)benzodiazepine-1-acetonitrile.
 5. The process of claim 2 wherein the compound is 8-chloro-6-phenyl-4H-s-triazolo(4,3-a)-(1,4)benzodiazepine-1-acetonitrile.
 6. The process of claim 3 wherein the compound is 8-chloro-6-phenyl-4H-s-triazolo(4,3-a)-(1,4)benzodiazepine-1-acetonitrile. 